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TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival.

Chavali PL, Saini RK, Zhai Q, Vizlin-Hodzic D, Venkatabalasubramanian S, Hayashi A, Johansson E, Zeng ZJ, Mohlin S, Påhlman S, Hansford L, Kaplan DR, Funa K - Cell Death Dis (2014)

Bottom Line: We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation.In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues.Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.

View Article: PubMed Central - PubMed

Affiliation: 1] Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden [2] Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

ABSTRACT
Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity. In tumor spheres, TLX is coexpressed with the neural progenitor markers Nestin, CD133 and Oct-4. In addition, TLX is coexpressed with the migratory neural progenitor markers CD15 and matrix metalloproteinase-2 (MMP-2) in xenografts of primary NB cells from patients. Subsequently, we show the effect of TLX on the proliferative, invasive and migratory properties of IMR-32 cells. We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation. In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues. Further, the Kaplan-Meier estimator indicated a negative correlation between TLX expression and survival in 88 NB patients. Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.

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Related in: MedlinePlus

TLX is expressed strongly in NB tissues and correlates with poor survival. (a) Low magnification ( × 1) of the whole tissue array stained for TLX. Identity of tissues is described below. Representative photomicrographs of normal peripheral nerve tissue and NB tissue in tissue array are immunostained for TLX (brown) and then counterstained with light green. Magnification, × 40. (b) Kaplan–Meier analysis of the data from 88 cases of NB, indicating negative correlation of NR2E1 expression with survival
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fig7: TLX is expressed strongly in NB tissues and correlates with poor survival. (a) Low magnification ( × 1) of the whole tissue array stained for TLX. Identity of tissues is described below. Representative photomicrographs of normal peripheral nerve tissue and NB tissue in tissue array are immunostained for TLX (brown) and then counterstained with light green. Magnification, × 40. (b) Kaplan–Meier analysis of the data from 88 cases of NB, indicating negative correlation of NR2E1 expression with survival

Mentions: We further examined if we could capture an enrichment of TLX expression in patient samples. For this, we screened NB tumor tissue arrays including 10 human cases (ages 5–48 years, two tissues per case) of aggressive NB and two cases of normal peripheral nervous tissues (PNS) for the expression of TLX (Figure 7a). There was an enhanced TLX expression in these tumors compared with normal PNS tissue. We also used the open R2 statistics application (microarray analysis and visualization platform; http://r2.amc.nl) using microarray data from 88 cases of NB-Versteeg-88 MAS5.0-u133p2 (http://hgserver1.amc.nl/cgi-bin/r2/main.cgi). A Kaplan–Meier analysis indicated that the higher expression of TLX (NR2E1) correlates with shorter survival of NB patients, with a cutoff at 8.3, χ2=9.98, d.f.=1, P=0.0016 (Figure 7b).


TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival.

Chavali PL, Saini RK, Zhai Q, Vizlin-Hodzic D, Venkatabalasubramanian S, Hayashi A, Johansson E, Zeng ZJ, Mohlin S, Påhlman S, Hansford L, Kaplan DR, Funa K - Cell Death Dis (2014)

TLX is expressed strongly in NB tissues and correlates with poor survival. (a) Low magnification ( × 1) of the whole tissue array stained for TLX. Identity of tissues is described below. Representative photomicrographs of normal peripheral nerve tissue and NB tissue in tissue array are immunostained for TLX (brown) and then counterstained with light green. Magnification, × 40. (b) Kaplan–Meier analysis of the data from 88 cases of NB, indicating negative correlation of NR2E1 expression with survival
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4237266&req=5

fig7: TLX is expressed strongly in NB tissues and correlates with poor survival. (a) Low magnification ( × 1) of the whole tissue array stained for TLX. Identity of tissues is described below. Representative photomicrographs of normal peripheral nerve tissue and NB tissue in tissue array are immunostained for TLX (brown) and then counterstained with light green. Magnification, × 40. (b) Kaplan–Meier analysis of the data from 88 cases of NB, indicating negative correlation of NR2E1 expression with survival
Mentions: We further examined if we could capture an enrichment of TLX expression in patient samples. For this, we screened NB tumor tissue arrays including 10 human cases (ages 5–48 years, two tissues per case) of aggressive NB and two cases of normal peripheral nervous tissues (PNS) for the expression of TLX (Figure 7a). There was an enhanced TLX expression in these tumors compared with normal PNS tissue. We also used the open R2 statistics application (microarray analysis and visualization platform; http://r2.amc.nl) using microarray data from 88 cases of NB-Versteeg-88 MAS5.0-u133p2 (http://hgserver1.amc.nl/cgi-bin/r2/main.cgi). A Kaplan–Meier analysis indicated that the higher expression of TLX (NR2E1) correlates with shorter survival of NB patients, with a cutoff at 8.3, χ2=9.98, d.f.=1, P=0.0016 (Figure 7b).

Bottom Line: We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation.In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues.Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.

View Article: PubMed Central - PubMed

Affiliation: 1] Sahlgrenska Cancer Center at the Sahlgrenska Academy, University of Gothenburg, Box 425, Gothenburg SE 40530, Sweden [2] Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.

ABSTRACT
Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity. In tumor spheres, TLX is coexpressed with the neural progenitor markers Nestin, CD133 and Oct-4. In addition, TLX is coexpressed with the migratory neural progenitor markers CD15 and matrix metalloproteinase-2 (MMP-2) in xenografts of primary NB cells from patients. Subsequently, we show the effect of TLX on the proliferative, invasive and migratory properties of IMR-32 cells. We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation. In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues. Further, the Kaplan-Meier estimator indicated a negative correlation between TLX expression and survival in 88 NB patients. Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.

Show MeSH
Related in: MedlinePlus